Immune Response on Optimal Timing and Fractionation Dose for Hypofractionated Radiotherapy in Non-Small-Cell Lung Cancer.
Immune Response on Optimal Timing and Fractionation Dose for Hypofractionated Radiotherapy in Non-Small-Cell Lung Cancer.
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DOI：
10.3389/fmolb.2022.786864
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发表时间：
2022
影响因子：
5
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Zhao X;Li J;Zheng L;Yang Q;Chen X;Chen X;Yu Y;Li F;Cui J;Sun J
背景：免疫检查点抑制剂(ICIS)的介入时机和放射治疗的分割是影响临床疗效的关键因素。本研究旨在探讨非小细胞肺癌(NSCLC)低分割放射治疗(HFRT)后不同时点、不同分割剂量肿瘤免疫微环境(TIME)的动态变化。方法：在植入小鼠模型中，实验组分别接受3.7Gy4次、4.6Gy3次、6.2Gy2次和10Gy1次的高频放射治疗，生物等效剂量(BED)为2 0Gy.比较肿瘤体积和生存期与对照组的差异。采用流式细胞术检测放疗后不同时间点的尾血和48h的肿瘤组织中免疫细胞及其PD-1/PD-L1的表达。非小细胞肺癌患者采用40Gy4次不同分割放射治疗，连续4天检测外周血免疫细胞、PD-1/PD-L1和细胞因子。结果：与对照组相比，各实验组肿瘤体积均明显缩小，6.2Gy×2F照射组生存时间显著延长(p<；0.05)。小鼠尾端血中CD8+T细胞计数在4.6Gy3次和6.2Gy2次照射后从48h增加到3周，CD8+PD-1在6.2Gy2次和10Gyx1F照射后从48h增加到2周(p<；0.05)。树突状细胞(DC)在2~3周被招募(p<；0.01)。非小细胞肺癌患者外周血CD8+T细胞计数和PD-1表达在6.2Gy4次照射后24h开始升高，CD8+T细胞计数在10Gy2F照射后96h开始升高(P<0.05)。6.2Gy×4F和10Gy×2F照射后48h试探性地收集DC细胞，并从24h开始增强PD-L1的表达(p<；0.05)。此外，6.2Gy4次照射后血清IL-10从24小时开始升高(p<；0.05)。相反，10Gy2次照射后24小时和96小时血清IL-4水平下降(p<；0.05)。结论：HFRT可诱导CD8+T细胞数量增加，免疫细胞因子阳性反应在特定时间段和分次剂量范围内均有增加。从48小时到2周是免疫应答的最佳时间窗，尤其是6.2Gy超分割。最好的免疫应答是96h后10Gy分次，两次而不是一次剂量。在这一时间窗口内，免疫治疗的干预可能会取得更好的效果。
Background: The intervention timing of immune checkpoint inhibitors (ICIs) and radiotherapy fractionations are critical factors in clinical efficacy. This study aims to explore dynamic changes of the tumor immune microenvironment (TIME) after hypofractionated radiotherapy (HFRT) at different timepoints and fractionation doses in non–small-cell lung cancer (NSCLC). Methods: In the implanted mouse model, the experimental groups received HFRT 3.7 Gy × 4 F, 4.6 Gy × 3 F, 6.2 Gy × 2 F, and 10 Gy × 1 F, respectively, with the same biological equivalent dose (BED) of 20Gy. Tumor volume and survival time were compared with those of the control group. Flow cytometry was performed to detect immune cells and their PD-1/PD-L1 expressions using tail-tip blood at different timepoints and tumor tissues at 48 h after radiotherapy. In NSCLC patients, immune cells, PD-1/PD-L1, and cytokines were detected in peripheral blood for 4 consecutive days after different fractionation radiotherapy with the same BED of 40Gy. Results: Tumor volumes were significantly reduced in all experimental groups compared with the control group, and the survival time in 6.2 Gy × 2 F (p < 0.05) was significantly prolonged. In tail-tip blood of mice, CD8+ T counts increased from 48 h to 3 weeks in 4.6 Gy × 3 F and 6.2 Gy × 2 F, and CD8+ PD-1 shortly increased from 48 h to 2 weeks in 6.2 Gy × 2 F and 10 Gy × 1 F (p < 0.05). Dentritic cells (DCs) were recruited from 2 to 3 weeks (p < 0.01). As for NSCLC patients, CD8+ T counts and PD-1 expression increased from 24 h in 6.2 Gy × 4 F, and CD8+ T counts increased at 96 h in 10 Gy × 2 F (p < 0.05) in peripheral blood. DC cells were tentatively recruited at 48 h and enhanced PD-L1 expression from 24 h in both 6.2 Gy × 4 F and 10 Gy × 2 F (p < 0.05). Besides, serum IL-10 increased from 24 h in 6.2 Gy × 4 F (p < 0.05). Conversely, serum IL-4 decreased at 24 and 96 h in 10 Gy × 2 F (p < 0.05). Conclusion: HFRT induces the increase in CD8+ T cells and positive immune cytokine response in specific periods and fractionation doses. It was the optimal time window from 48 h to 2 weeks for the immune response, especially in 6.2 Gy fractionation. The best immune response was 96 h later in 10 Gy fractionation, delivering twice instead of a single dose. During this time window, the intervention of immunotherapy may achieve a better effect.
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DOI：
10.1038/nrclinonc.2015.120
发表时间：
2015-09
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Schaue D;McBride WH
通讯作者：
McBride WH
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
20.3
作者：
Fujii, S;Shimizu, K;Lotze, MT
通讯作者：
Lotze, MT
影响因子：
28.4
作者：
Aggarwal, Charu;Thompson, Jeffrey C.;Carpenter, Erica L.
通讯作者：
Carpenter, Erica L.
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S